1. Field of the Invention
This invention relates to a complex and an asymmetric catalyst using such a complex, and more particularly to an asymmetric catalyst high-enantioselectively promoting an epoxidation reaction of an amide or a ketone. Furthermore, the invention relates to a method for producing epoxides by using the asymmetric catalyst.
2. Description of Related Art
The epoxidation means a reaction for oxidatively changing an alkene to an epoxide by adding one oxygen atom to carbon-carbon double bond. As such an epoxidation method is known a method that the epoxidation is carried out in an inert organic solvent such as dichloromethane or the like by using an organic peracid as an epoxidizing agent.
There is recently known a method for synthesizing an optically active epoxide by catalytically oxidizing a prochiralic alkene with an asymmetric catalyst. This method using the asymmetric catalyst is a very important technique because it is possible to supply a great amount of an optically active compound from a tiny amount of the asymmetric catalyst.
Also, an epoxidation method using a cinnamate as a substrate of the catalyst.
However, an industrially mass-producible method is not known up to the present time. Furthermore, there are problems in the generality of the substrate. That is, only the cinnamate is known as the substrate of catalyst, so that there is a problem that the conventional catalyst used in the cinnamate can not be applied to a general substrate other than the cinnamate. Because, when the conventional catalyst is applied to a substrate containing a functional group such as carbon-carbon double bond, ketone or the like in its molecule, since such a catalyst is very high in the reactivity, a side reaction with such a functional group is caused and hence it is impossible to achieve an adequate epoxidation reaction.
Therefore, even if a compound containing a functional group such as carbon-carbon double bond, ketone or the like in its molecule is used as a substrate, it is desired to develop a method of producing an epoxide by using a catalyst capable of promoting the epoxidation reaction. If such a method is established, it is possible to simply synthesize an optically active compound useful for drug medicines in a large quantity. However, a convenient method for producing epoxide is no existence at this moment.
It is, therefore, an object of the invention to provide a general and multi-purpose method of producing an epoxide.
In order to achieve the above object, the inventors have made developments of asymmetric catalysts in the catalytic asymmetric epoxidation of unsaturated compounds and studies on the estimation of reactivity using calculation chemistry, and found out the following complexes and a method for producing an epoxide by using such a complex as a catalyst.
The complex according to the invention is characterized by representing the following general formula (I): 
wherein X is P or As, and M is a rare earth metal, and R1 is an alkoxy group or an alkyl peroxy group, and R2 is a residue of a phenyl derivative, a residue of a heterocyclic compound or an alkyl group, and each of R3 and R4 is a substituent on an aromatic ring.
Also, the complex according to the invention is characterized by representing the following general formula (II): 
wherein X is P or As, and M is a rare earth metal, and R2 is a residue of a phenyl derivative, a residue of a heterocyclic compound or an alkyl group, and each of R3 and R4 is a substituent on an aromatic ring.
Furthermore, the complex according to the invention is characterized by representing the following general formula (III): 
wherein X is P or As, and M is a rare earth metal, and R2 is a residue of a phenyl derivative, a residue of a heterocyclic compound or an alkyl group, and each of R3 and R4 is a substituent on an aromatic ring.
In a preferable embodiment of the invention, M is at least one selected from the group consisting of La, Sm, Dy, Yb.
The asymmetric catalyst according to the invention is characterized by comprising the complex represented by the above general formula (I), (II) or (III).
The method for producing epoxide according to the invention is characterized by reacting an unsaturated amide or an unsaturated ketone with an oxidizing agent in the presence of the above asymmetric catalyst.
In a preferable embodiment of the method according to the invention, the unsaturated amide is an xcex1,xcex2-unsaturated active amide having a nitrogen-containing heterocycle such as an imidazole derivative, an oxazolidinon or the like.
In another preferable embodiment of the method according to the invention, the unsaturated ketone is at least one selected from the group consisting of trans-xcex1,xcex2-unsaturated ketones, cis-xcex1,xcex2-unsaturated ketones, xcex1,xcex2,xcex3,xcex4-unsaturated ketones.
In the other preferable embodiment of the method according to the invention, the oxidizing agent is at least one selected from the group consisting of t-butyl hydroperoxide (TBHP), cumene hydroperoxide (CMHP) and trityl hydroperoxide (TrOOH).
In a further preferable embodiment of the method according to the invention, the reaction is carried out in the presence of a coordinating solvent.
In a still further preferable embodiment of the method according to the invention, the coordinating solvent is selected from the group consisting of tetrahydrofuran (THF), dimethoxyethane and ether.
In a yet further preferable embodiment of the method according to the invention, the reaction is further carried out with an alcohol, a metallic amide, a reducing agent, a metallic enolate or the like to obtain an xcex1,xcex2-epoxy ester, an xcex1,xcex2-epoxy amide, an xcex1,xcex2-epoxy aldehyde and xcex3,xcex4-epoxy-xcex2-ketoester.
The complex according to the invention is represented by the general formula (I): 
wherein X is P or As, and M is a rare earth metal, and R1 is an alkoxy group or an alkyl peroxy group, and R2 is a residue of a phenyl derivative, a residue of a heterocyclic compound or an alkyl group, and each of R3 and R4 is a substituent on an aromatic ring.
Also, the complex according to the invention is represented by the general formula (II): 
wherein X is P or As, and M is a rare earth metal, and R2 is a residue of a phenyl derivative, a residue of a heterocyclic compound or an alkyl group, and each of R3 and R4 is a substituent on an aromatic ring.
Furthermore, the complex according to the invention is represented by the general formula (III): 
wherein X is P or As, and M is a rare earth metal, and R2 is a residue of a phenyl derivative, a residue of a heterocyclic compound or an alkyl group, and each of R3 and R4 is a substituent on an aromatic ring.
The inventors have focused attention on substrates other than cinnamate in view of the generality of the substrate. However, the conventionally used catalyst is very low in the functional group selectivity, so that it can not be applied to a substrate containing a functional group such as carbon-carbon double bond, ketone or the like.
Therefore, the inventors have attempted to develop various sorts of the catalyst for the epoxidation of unsaturated compounds and found out that the aforementioned complexes are effective as the catalyst.
In the above formulae (I)-(III), M is a rare earth metal. The rare earth metal is not particularly limited. As the rare earth metal, mention may be made of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Dy, Ho, Er and Yb. From a viewpoint of a higher enantioselectivity, at least one selected from the group consisting of La, Sm, Dy, Yb is preferable as the rare earth metal.
Also, each of R3 and R4 is a substituent on an aromatic ring and is not particularly limited. As the substituent, mention may be made of an alkyl group, an ether, a halogen atom, an amido group, an ester and so on.
The complex having a bone structure of the above formula (I), (II) or (III) can be synthesized as follows.
That is, the complex can be obtained by reacting a metal isopropoxide, an optically active binaphthol and triphenyl oxide in a solvent such as THF or the like at room temperature for from 30 minutes to 1 hour.
In case of the complex (1:1:1) shown in the formula (I), a ratio of metal isopropoxide to optically active binaphthol (BINOL derivative) to triphenyl oxide is about 1:about 1:about 1. In view of a higher reactivity, the ratio is preferable to be metal isopropoxide:BINOL derivative:triphenyl oxide=about 100 mol %:about 100 mol %:about 100 mol %.
In case of the complex (1:2:2) shown in the formula (II), a ratio of metal isopropoxide to optically active BINOL derivative to triphenyl oxide is about 1:about 2:about 2. In view of the stability of the complex in the solution, the ratio is preferable to be metal isopropoxide:BINOL derivative:triphenyl oxide=about 100 mol %:about 200 mol %:about 200 mol %.
In case of the complex (1:2:3) shown in the formula (III), a ratio of metal isopropoxide to optically active BINOL derivative to triphenyl oxide is about 1:about 2:about 3. From a viewpoint that the crystallization of the complex is made easy, the ratio is preferable to be metal isopropoxide:BINOL derivative:triphenyl oxide=about 100 mol %:about 100 mol %:about 300 mol %.
Especially, the excessive amount of the metal isopropoxide promotes the epoxidation reaction as mentioned later. Therefore, if it is intended to promote the epoxidation reaction, the ratio of the metal isopropoxide is made high. For example, it is desirable to increase the ratio of the metal isopropoxide up to 1 equivalent with respect to a chiral ligand in order to promote the reaction.
The thus obtained complex acts as an asymmetric catalyst. The asymmetric catalyst according to the invention comprises the complex represented by the above formula (I), (II) or (III). The above conditions of the metal mentioned on the complex can be applied for the catalyst. The asymmetric catalyst means a catalyst itself having an ability of producing an optically active substance, rightly an enantio-separating catalyst. The asymmetric catalyst according to the invention can epoxidize an unsaturated amide or an unsaturated ketone high-enantioselectively as mentioned later.
Next, the method for producing an epoxide according to the invention will be explained. According to the invention, the epoxide can be obtained by reacting the unsaturated amide or unsaturated ketone with an oxidizing agent in the presence of the asymmetric catalyst. The term xe2x80x9cunsaturatedxe2x80x9d used herein means a so-called carbon-carbon double bond.
In the epoxidation reaction of the unsaturated amide, epoxy peroxy ester is a stable intermediate produced in the reaction system and can be reacted with an alcohol, a metal amide, a reducing agent, an enolate or the like to easily provide xcex1,xcex2-epoxy ester, xcex1,xcex2-epoxy amide, xcex1,xcex2-epoxy aldehyde, xcex3,xcex4-epoxy xcex2-keto ester, so that it is an intermediate having a very high versatility. In this case, methanol or the like may be mentioned as the alcohol.
The unsaturated amide or unsaturated ketone intended for the asymmetric catalyst according to the invention is not particularly limited. As the unsaturated ketone, mention may be made of any unsaturated ketones including unsaturated aliphatic ketones, unsaturated aromatic ketones and the like. For example, the unsaturated ketone may include at least one selected from the group consisting of trans-xcex1,xcex2-unsaturated ketones, cis-xcex1,xcex2-unsaturated ketones and xcex1,xcex2,xcex3,xcex4-unsaturated ketones.
As the unsaturated amide, mention may be made of unsaturated active amides having a nitrogen-containing heterocycle such as imidazole derivatives, oxazolidinone and the like.
As the oxidizing agent may be mentioned a peroxide. The peroxide may include t-butyl hydroperoxide (TBHP), cumene hydroperoxide (CMHP), trityl hydroperoxide (TrOOH) and so on. Among them, TBHP is preferable as the oxidizing agent from a viewpoint of a high reactivity.
A solvent used in the epoxidation reaction is not particularly limited. As the solvent, mention may be made of a low-polarity solvent such as toluene, CH2Cl2 or thelike, and a coordination solvent such as tetrahydrofuran (THF), dimethoxyethane, ether or the like. In view of the rise of the reaction rate, tetrahydrofuran (THF) is preferable as the solvent.
The reaction temperature for the epoxidation reaction is not particularly limited, but is 0-40xc2x0 C., preferably 15-25xc2x0 C. from a viewpoint of a high enantioselectivity. The lower limit of 0xc2x0 C. is for maintaining the reactivity of the epoxidation reaction, and the upper limit of 40xc2x0 C. is for stabilizing the complex and TBHP.
Furthermore, the concentration of the amide or ketone is not particularly limited and may be properly changed in accordance with the interest product. The reaction rate tends to become high as the concentration of the amide or ketone is high. However, the reaction rate does not increase even if the concentration of the substrate or the concentration of the amide or ketone is so increased after the arrival to a maximum reaction rate because the concentration of the substance is saturated in the vicinity of the maximum reaction rate.
Moreover, various additives may be added to the reaction solution. For example, a drying agent such as MS4A or the like may be added.
MS is one of crystalline zeolites and there are 3A, 4A, 5A and so on in accordance with the pore size in the crystal. For example, 4A means that the pore size is about 4 angstroms. A main function of MS is for incorporating water in the reaction solution into the pores to remove a slight amount of water.